.beta.-Lactam derivatives used as antibiotics generally have carboxyl groups within their molecules and, in many instances, are put to use as the free carboxylic acids or with the carboxyl groups protected in the form of pharmaceutically acceptable salts. However, in the process of synthesis of .beta.-lactam antibiotics, such carboxyl groups are usually protected with suitable protective groups, which must be ultimately eliminated in good yield without affecting the other moiety of the molecule.
A .beta.-lactam derivative having a protected carboxyl group may be represented by the general formula: ##STR3## wherein R.sup.1 is a hydrogen atom, a lower alkoxy group or a formamido group; R.sup.2 is a hydrogen atom, a halogen atom, an amino group, an amido group or an imido group; ##STR4## R.sup.3 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkoxyl group, a substituted or unsubstituted vinyl group, a lower alkoxymethyl group, acetoxymethyl group, carbamoyloxymethyl group, a heterocyclethiomethyl group, 5-methyltetrazol-2-ylmethyl group, 1-methylpyrrolidinomethyl group or pyridiniummethyl group; R.sup.4 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkoxyl group, a lower acyloxyl group, a lower alkylthio group or a heterocycle-thio group; n is 0, 1 or 2; and X is selected from the group consisting of a benzyl group having a hydroxyl group, a lower alkyl group or a lower alkoxy group as a phenyl ring substituent, a diphenylmethyl group, a diphenylmethyl group having a hydroxyl group, a lower alkyl group or a lower alkoxy group as a phenyl ring substituent, or tert-butyl. Heretofore elimination of the carboxyl-protecting group X from the .beta.-lactam derivative to give a .beta.-lactam derivative of the general formula: ##STR5## wherein R.sup.1 and R.sup.2 are as defined above, ##STR6## is accomplished by subjecting the .beta.-lactam derivative of general formula (II) to catalytic reduction using a noble metal catalyst or to treatment with an acid, for instance. The latter method includes such versions as one using trifluoroacetic acid (Journal of The American Chemical Society 91, 5674, 1969), one using formic acid (Chemical Pharmaceutical Bulletin 30, 4545, 1982), the method in which the starting compound is reacted with aluminum chloride in the presence of anisole (Tetrahedron Letters 2793, 1979) and so on. However, these prior art methods have the following disadvantages.
Referring, first, to the catalytic reduction using a noble metal catalyst, .beta.-lactam antibiotics generally contain a sulfide bond which may act as a catalyst poison and, therefore, the expensive noble metal catalyst must be used in a large amount. Furthermore, this method cannot be applied to .beta.-lactam antibiotics containing reducible groups such as nitro, a carbon-to-carbon multiple bond or the like. Moreover, when the protective group is a tert-butyl group, it cannot be eliminated by this method. Further, when the protective group is a benzyl group having a hydroxy group, a lower alkyl group or a lower alkoxy group as a phenyl ring substituent or a diphenylmethyl group having a hydroxy group, a lower alkyl group or a lower alkoxy group as a phenyl ring substituent, this method fails to eliminate these groups in many instances.
The method using an acid also has the disadvantage that it requires at least a stoichiometric amount of strong acid despite the fact that the .beta.-lactam derivative of general formula (I) is unstable to acid, with the result that the .beta.-lactam derivative of general formula (I) once produced by the method is decomposed to detract from its ultimate yield.
For example, when a p-methoxybenzyl group masking the carboxyl group of cephalosporin compound of the formula (III) given below is to be eliminated with trifluoroacetic acid, this expensive reagent trifluoroacetic acid must be used generally in an amount of at least 5 molar equivalents relative to the cephalosporin compound of general formula (III). With an equimolar amount of trifluoroacetic acid, for instance, the above reaction does not substantially proceed. Suppose that the cephalosporin of formula (III) were deprotected with a large amount of trifluoroacetic acid and, after the reaction, one tried to recover the triflurroacetic acid for reuse, a substantial loss of the acid would be inevitable. Furthermore, in the course of the recovery procedure, the acid-labile compound of the following formula (IV) would be decomposed to further detract from the reaction yield. ##STR7##
The method employing formic acid also has a similar disadvantage. Thus, the expensive reagent formic acid of 98 to 100% concentration must be used in large excess as a reaction solvent. And if vacuum distillation, for instance, be carried out for its recovery and reuse, the acid-labile compound of the above formula (IV) would be decomposed to detract from its yield.
The method which comprises reacting the protected compound with aluminum chloride in the presence of anisole has the following disadvantages. It is essential to use aluminum chloride which, however, is difficult to handle because it tends to undergo exothermic reaction with atmospheric moisture to give rise to hydrochloric acid. Furthermore, as the reaction mixture is rendered strongly acidic during the reaction or the subsequent workup procedure, the acid-labile compound of general formula (IV) is decomposed so that the yield of the compound is adversely affected. In addition, in the workup procedure after the reaction, a large amount of aluminum hydroxide must be disposed of.
It is, thus, clear that there is not available a method by which a carboxyl-protecting group X can be eliminated from a carboxy-protected .beta.-lactam derivative of general formula (II) to give a .beta.-lactam derivative of general formula (I) in good yield and without difficulties on a commercial scale.